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Biology of Reproduction 60, 164-168 (1999)
©Copyright 1999 Society for the Study of Reproduction, Inc.

Effect of Stress-Like Concentrations of Cortisol on Estradiol-Dependent Expression of Gonadotropin-Releasing Hormone Receptor in Orchidectomized Sheep1

T.E. Adams2,a, H. Sakuraia, and B.M. Adamsa

a Department of Animal Science, University of California, Davis, California 95616


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The effect of stress-like concentrations of cortisol (C) on estrogen-dependent expression of GnRH receptor was evaluated using orchidectomized sheep (wethers; n = 6 animals per group). C (5.0 mg/50 kg per hour; groups 1–4) or a comparable volume of vehicle (groups 5–8) was delivered by continuous infusion for 48 h. During the final 24 h of infusion, animals received concurrent infusion of estradiol (E2) at rates of 0 (groups 1 and 5), 0.5 (groups 2 and 6), 2.0 (groups 3 and 7), or 8.0 (groups 4 and 8) µg/50 kg per hour. Pituitary tissue was collected at the end of infusion. Although C did not affect (p > 0.05) the basal concentration of GnRH receptor or GnRH receptor mRNA, it reduced (p < 0.05) the increase in receptor and receptor mRNA induced by concurrent administration of 0.5 µg E2/50 kg per hour. In contrast, the increase in GnRH receptor expression induced by higher levels of estrogen stimulation was not affected (p > 0.05) by concurrent administration of C. The effect of C on the temporal pattern of E2-dependent increase in GnRH receptor expression was assessed using wethers receiving E2 (0.5 µg/50 kg per hour) by continuous infusion for 0 (groups 1 and 5), 24 (groups 2 and 6), 48 (groups 3 and 7), or 72 h (groups 4 and 8). Animals received C (5.0 mg/50 kg per hour; groups 1–4) or vehicle (groups 5–8) beginning 24 h before, and continuing throughout, the E2 delivery period. Stress-like concentrations of C reduced (p < 0.05) the increase in GnRH receptor and receptor mRNA induced after 24 h of E2 stimulation. However, the suppressive effect of C was transient, and tissue levels of GnRH receptor and receptor mRNA were comparable after 72 h of E2 infusion in animals receiving C or vehicle alone. Collectively these observations demonstrate that C suppresses estrogen-dependent increase in tissue concentrations of GnRH receptor and receptor mRNA. However, this effect of C is transient and not evident in animals receiving moderate to high levels of estrogen stimulation. This transient suppression of GnRH receptor expression may account, at least in part, for the anti-gonadal effect of glucocorticoids.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Stressful stimuli increase the activity of the hypothalamo-pituitary-adrenal axis in rodents [1–3], primates [4–6], and domestic species [7–9] and commonly lead to a marked and persistent increase in glucocorticoid secretion. Another physiological correlate that often accompanies repetitive or prolonged exposure to stress is reduced fertility and suppressed gonadotropin secretion [5, 10–13]. Although the cellular or biochemical basis for the anti-gonadal effect of stress has not been fully characterized, several studies indicate that glucocorticoids act at hypothalamic and hypophyseal loci to decrease gonadotropin secretion.

Glucocorticoids reportedly act directly at hypothalamic sites to suppress GnRH synthesis [14] and decrease the activity of the GnRH pulse-generating center [15]. Similarly, glucocorticoids act directly at pituitary loci to reduce the sensitivity or responsiveness of the gonadotroph cells to GnRH [16, 17]. The tissue concentration of GnRH receptor is generally considered to be one of several key determinants of gonadotroph responsiveness [18, 19]. Estrogen-dependent augmentation of tissue concentration of GnRH receptor is associated with enhanced responsiveness [20]. We have previously demonstrated [21] that the estradiol (E2)-dependent increase in pituitary concentrations of GnRH receptor is suppressed in castrated male sheep (wethers) receiving stress-like concentrations of cortisol (C). Surprisingly, this C-dependent attenuation of GnRH receptor expression occurs in the absence of any reduction in the magnitude of E2-induced increase in the tissue concentrations of GnRH receptor mRNA. This divergence between E2-induced augmentation of GnRH receptor and GnRH receptor mRNA suggests that glucocorticoids may act at posttranscriptional sites to reduce GnRH receptor synthesis or selectively increase receptor degradation. Alternatively, glucocorticoids may delay, but not eliminate, the onset of estrogen-dependent transcription and translation.

In the work presented here we examined the temporal pattern of estrogen-induced increase in GnRH receptor and GnRH receptor mRNA in wethers receiving stress-like concentrations of C. In these studies, continuous infusion of C was used to establish a stable serum concentration of C that approximated the serum concentration noted in sheep during hypoglycemic or endotoxemic stress [7–9]. We also used i.v. delivery of graded levels of E2 to establish serum concentrations of E2 that span the physiological range in male [22, 23] and female [24] sheep. We hypothesized that stress-like concentrations of C would effect prolonged suppression of the estrogen-dependent increase in tissue concentrations of GnRH receptor in a manner that was not affected by the duration or magnitude of estrogenic stimulation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

The effect of stress-like concentrations of C on E2-dependent increase in pituitary tissue concentrations of GnRH receptor and GnRH receptor mRNA was assessed using orchidectomized sheep (wethers; University of California, Davis, flock) at approximately 6–8 mo of age. The wethers were castrated within 2 wk of birth and were housed in an open-sided barn under natural lighting. Wethers were afforded free access to water and alfalfa pellets supplemented with cereal grains and vitamin and mineral premix. These studies were conducted during the spring and summer, periods of low reproductive activity in sheep at this latitude (38°N). All experimental procedures involving the use of animals were conducted in accordance with NIH Guidelines and were reviewed and approved by the Animal Use and Care Committee for the University of California, Davis.

Cannulation

Prior to experimentation, polyethylene cannulae (Intramedic PE 190; Clay Adams, Parsippany, NJ) were inserted into the left jugular vein to serve as hormone delivery cannulae (C or E2). In experiments 2 and 3, an additional cannula, inserted into the contralateral vein, was used for blood collection. All cannulae were passed through a protective plastic tubing sheath to the exterior of the animal holding area. Animals were freely mobile at the end of a 1-m lead. The cannulae were inserted 3 days prior to initiation of treatment to permit acclimation to the conditions of experimentation.

Hormone Delivery

Cannulae for the delivery of C and E2 were connected to syringes placed in Harvard infusion pumps (Model 2265; Harvard Bioscience, South Natick, MA). C (Sigma Chemical Co., St. Louis, MO) in 50% ethanol-saline (C delivery vehicle [CV]) and E2 (Sigma) in 10% ethanol-saline (E2 delivery vehicle [EV]) were administered by continuous infusion. Control animals received comparable volumes of the appropriate vehicle.

Experiment 1

The time course of E2-dependent change in steady-state concentrations of GnRH receptor and GnRH receptor mRNA was assessed using 36 wethers assigned to 1 of 6 groups (n = 6 animals per group). Animals in groups 2–6 received E2 (2 µg E2/50 kg per hour) as a continuous infusion. Control wethers (group 1) were infused with vehicle alone. Anterior pituitary tissue was collected after 1.5, 3, 6, 12, or 24 h of E2 infusion in groups 2–6, respectively. Pituitary tissue was collected from control animals (group 1) after 24 h of vehicle infusion. Animals were stunned by means of a captive bolt pistol and killed by exsanguination immediately before tissue collection. After removal, pituitary tissue was halved by a midsagittal cut, and each half was immediately frozen in liquid nitrogen and stored at -80°C for later analysis. Blood, collected during exsanguination, was allowed to clot on ice, and serum was removed within 24 h of collection. Serum samples were rapidly frozen and stored at -20°C for later analysis.

Experiment 2

The effect of stress-like concentrations of C on the sensitivity of the estrogenic response was examined using 48 wethers assigned at random to 1 of 8 treatment groups (n = 6 wethers per group). C (5.0 mg/50 kg per hour; groups 1–4) or a comparable volume of CV (groups 5–8) was delivered by continuous infusion for 48 h. During the final 24 h of infusion, animals received concurrent infusion of E2 at rates of 0 (groups 1 and 5), 0.5 (groups 2 and 6), 2.0 (groups 3 and 7), or 8.0 (groups 4 and 8) µg/50 kg per hour. Blood samples were collected at 4-h intervals during the infusion period, and anterior pituitary tissue was collected at the end of infusion. The tissue and blood were processed and stored as described above.

Experiment 3

The effect of C on the temporal pattern of E2-dependent increase in GnRH receptor expression was assessed using 48 wethers assigned at random to 1 of 8 treatment groups (n = 6 wethers per group). E2 (0.5 µg/50 kg per hour) was delivered by continuous infusion for 0 (groups 1 and 5), 24 (groups 2 and 6), 48 (groups 3 and 7), or 72 h (groups 4 and 8). Animals received C (5.0 mg/50 kg per hour; groups 1–4) or a comparable volume of CV (groups 5–8) beginning 24 h before initiation E2 of infusion. Intravenous administration of C was continued throughout the E2 delivery period. Pituitary tissue was collected at the end of infusion. The tissue was processed and stored as described above.

Endocrine Analysis

Serum concentrations of E2 and C were determined using previously validated RIA procedures [24, 25]. Intra- and interassay coefficients of variation were less than 10%. The minimum sensitivity of the E2 and C assays was 0.6 pg/ml and 1 ng/ml, respectively.

The affinity and tissue concentration of GnRH receptor were determined by means of the procedure previously described [20, 26]. Tissue concentrations of GnRH receptor mRNA were determined using the RNase protection assay described previously [27]. A plasmid containing a cDNA insert for the ovine GnRH receptor [28] was kindly provided by Dr. J. Brooks (MRC Reproductive Biology Unit, Edinburgh, UK). The sense and antisense cRNA were generated by in vitro transcription using either T7 RNA or SP6 RNA polymerase and the Riboprobe Gemini System II reagent system (Promega Corp., Madison, WI).

Statistical Analyses

Statistical significance of treatments was assessed by ANOVA [29]. Where significant treatment effects were noted, mean comparisons were made using Duncan's multiple-range test. Data are presented in the text and figures as mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Serum Concentrations of C and E2

In these experiments, infusion of E2 at 0.5, 2.0, or 8.0 µg/50 kg per hour increased serum concentrations of E2 to 4.9 ± 0.3 pg/ml, 15.3 ± 0.5 pg/ml, and 56.1 ± 2.7 pg/ml, respectively, 1 h after the beginning of E2 delivery. Serum E2 was maintained at these concentrations for the remainder of the E2 infusion period. Serum concentrations of E2 were below the limits of detection (< 0.6 pg/ml) in wethers receiving EV alone. In experiments 2 and 3, infusion of C at a rate of 5.0 mg/50 kg per hour increased serum concentrations of C to 98.6 ± 3.8 ng/ml after 4 h of infusion. Serum levels of C were maintained at this level for the remainder of the infusion period. In contrast, serum concentrations of C were 12.5 ± 0.8 ng/ml in control animals receiving vehicle alone.

Time Course of the E2-Dependent Response

Steady-state concentrations of GnRH receptor and GnRH receptor mRNA in wethers receiving vehicle alone were 4.0 ± 0.2 fmol/mg fresh tissue equivalent and 1.0 ± 0.1 pg/µg total RNA, respectively. Continuous infusion of E2 resulted in an increase to 3.5- to 4-fold in steady-state concentrations of GnRH receptor and GnRH receptor mRNA (Fig. 1). Significant augmentation of tissue concentrations of GnRH receptor mRNA and GnRH receptor was first evident at 3 and 6 h, respectively, after beginning E2 infusion, and maximal tissue concentrations of GnRH receptor (15.3 ± 1.0 fmol/mg fresh tissue equivalent) and GnRH receptor mRNA (3.8 ± 0.3 pg/g total RNA) were evident 12 h after first introduction of E2. The affinity of the GnRH receptor (Ka = 3.2 ± 0.2 x 109 L/M) did not vary (p > 0.05) with duration of E2 exposure.



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  		FIG. 1. Temporal pattern of increase in the concentration of GnRH receptor (open circles) and GnRH receptor mRNA (closed circles) in pituitary tissue of orchidectomized sheep receiving E2 (2.0 µg/50 kg per hour) by continuous infusion.

Effect of C on E2-Induced GnRH Receptor Expression

Continuous infusion of E2 at 0.5, 2.0, or 8.0 µg/50 kg per hour for 24 h resulted in a dose-dependent increase in concentrations of GnRH receptor and GnRH receptor mRNA in pituitary tissue (Fig. 2). Tissue levels of receptor and receptor mRNA were significantly increased above basal levels in animals receiving E2 at a rate of 0.5 µg/50 kg per hour. Maximal concentrations of receptor and receptor mRNA were evident in wethers receiving E2 at 2.0 µg/50 kg per hour. Although stress-like concentrations of C did not affect (p > 0.05) basal concentrations of GnRH receptor or receptor mRNA, C reduced (p < 0.05) the extent of increase in tissue concentrations of receptor and receptor mRNA induced by concurrent administration of E2 at a rate of 0.5 µg/50 kg per hour. In contrast, the increase in GnRH receptor expression induced by higher levels of estrogen stimulation was not affected (p > 0.05) by concurrent administration of stress-like concentrations of C.



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  		FIG. 2. Effect of stress-like concentrations of C on the magnitude of increase in tissue concentrations of GnRH receptor and GnRH receptor mRNA induced by E2 in wethers. C (5.0 mg/50 kg per hour) or a comparable volume of vehicle was delivered by continuous infusion for 48 h. During the final 24 h of infusion, animals received concurrent infusion of E2 at various rates. Anterior pituitary tissue was collected at the end of the E2 infusion period (n = 6 wethers per group).

Effect of C on the Temporal Pattern of GnRH Receptor Expression

Pituitary concentrations of GnRH receptor and GnRH receptor mRNA in control wethers receiving E2 alone were increased to 2- to 3-fold 24 h after first introduction of E2, and tissue levels of receptor and receptor mRNA remained elevated after 48 and 72 h of estrogen stimulation (Fig. 3). In contrast, concurrent administration of E2 and stress-like concentrations of C significantly delayed the estrogenic response. A significant increase in tissue concentration of GnRH receptor mRNA was evident 48 h after first introduction of E2 in C-treated wethers. However, significant augmentation of tissue concentrations of GnRH receptor was not evident until 72 h after initiation of E2 administration.



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  		FIG. 3. Effect of C on the temporal pattern of E2-induced increase in tissue concentrations of GnRH receptor and GnRH receptor mRNA in pituitary tissue of wethers. E2 (0.5 µg/50 kg per hour) was delivered by continuous infusion for 0, 24, 48, or 72 h. Animals received C (5.0 mg/50 kg per hour) or a comparable volume of vehicle beginning 24 h before initiation of E2 infusion (n = 6 wethers per group). Intravenous administration of C was continued throughout the E2 delivery period. Anterior pituitary tissue was collected at the end of the infusion period.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although estrogen-dependent augmentation of pituitary concentrations of GnRH receptor and receptor mRNA is well documented [27, 30, 31], the time course of this response has not been precisely characterized. The data presented here, and elsewhere [20], indicate that the E2-dependent increase in pituitary concentration of GnRH receptor is rapid and complete within 12 h of first introduction of E2. We extend these observations by demonstrating that this rapid increase in tissue concentration of receptor is preceded by an even more acute increase in tissue levels of GnRH receptor mRNA. Estrogen-induced augmentation of GnRH receptor expression is evident in vitro [30, 32] and in animal models in which hypothalamic inputs are negated immunologically [31] or by hypothalamo-pituitary disconnection [33, 34]. These observations indicate that E2 is acting directly at hypophyseal sites to increase GnRH receptor expression.

The estrogen-dependent increase in tissue concentration of GnRH receptor mRNA may reflect increase in transcription and/or reduction in the rate of degradation. Although enhanced stability of GnRH receptor mRNA may account for a portion of the increase in steady-state concentrations of GnRH receptor mRNA noted during estrogen stimulation, increase in gene transcription is indicated by the report that estrogen-induced increase in GnRH receptor is blocked in pituitary tissue treated with inhibitors of transcription, such as actinomycin D [32].

The results presented here indicate that stress-like concentrations of C do not affect the basal level of GnRH receptor expression. However, the estrogen-induced increase in tissue concentrations of GnRH receptor and GnRH receptor mRNA is blunted in a manner that is dependent on the duration and magnitude of estrogen stimulation. C-dependent suppression of the gonadotroph response to estrogen is not evident at serum levels of E2 that approach, or exceed, the maximal level commonly noted in male or female sheep. However, stress-like concentrations of C block or delay the augmentation of tissue concentrations of GnRH receptor and GnRH receptor mRNA induced by a serum level of E2 comparable to that noted in mature rams [22, 23] and during the early follicular phase of the estrous cycle in ewes [24]. This observation indicates that sensitivity to stress or stress-like concentrations of C may vary with reproductive status, and it is consistent with our recent observation that exogenous C blocks, or delays, the preovulatory surge of LH in sheep [21].

The dose dependence of the C-induced suppression of the estrogenic response may indicate that the activated estrogen and glucocorticoid receptors are competing for common regulatory sites in the transcriptional complex. A similar competitive relationship between the activated estrogen and glucocorticoid receptors has recently been demonstrated in expression of the collagenase [35] and insulin-like growth factor-1 [36] genes. Alternatively, or additionally, the activated glucocorticoid receptor may directly modulate GnRH receptor gene transcription by direct attachment to a glucocorticoid response element in the promoter region. Although the composition of the sequence flanking the gene encoding the ovine GnRH receptor has not been determined, a glucocorticoid response element sequence has been identified in the promoter for the human [37, 38], but not the rodent [39, 40], GnRH receptor gene.

In addition to dependence on the level of estrogen stimulation, the observations detailed here demonstrate that the suppressive effect of C on estrogen-dependent GnRH receptor expression is transient. This suggests that persistent E2 stimulation overcomes the suppression induced by the glucocorticoid. The mechanism underlying the transient nature of the glucocorticoid response is unknown; however, persistent glucocorticoid stimulation is associated with down-regulation of the glucocorticoid receptor [41, 42]. This decrease in the tissue concentration of the glucocorticoid receptor may reduce the efficiency of competition at the regulatory sites in the promoter region of the GnRH receptor gene. Alternatively, persistent estrogenic stimulation may increase the formation of cellular factors that override C-dependent suppression. The transient nature of the glucocorticoid-dependent suppression of GnRH receptor expression is also similar to the short-lived effect of glucocorticoids on expression of the corticotropin-releasing hormone receptor in pituitary tissue [43, 44].

The results of our initial experiment indicate that E2-induced expression of GnRH receptor and that of GnRH receptor mRNA are tightly coupled in nonstressed animals. In contrast, an apparent decoupling is evident in animals receiving E2 and stress-like concentrations of C. This is most clearly evident after 48 h of estrogen stimulation. At this point C-dependent suppression of tissue concentrations of GnRH receptor mRNA has been reversed, but tissue concentrations of the receptor itself remain depressed. This disparity between the patterns of increase in GnRH receptor and GnRH receptor mRNA in C-treated animals suggests that C may act at transcriptional and posttranscriptional loci to impede GnRH receptor expression. Furthermore, release from transcriptional suppression appears more rapid than release from posttranscriptional inhibition. Although the posttranscriptional effects of glucocorticoids on GnRH receptor expression are, at this point, largely hypothetical, such effects may reflect C-dependent suppression of translation or C-dependent increase in receptor degradation. In this regard it may be important to note the results of a recent study demonstrating that glucocorticoids did not impair translation, but selectively increased protein degradation, in pancreatic tissue [45].

Collectively, the studies reported here demonstrate that E2 induces a rapid and marked increase in GnRH receptor expression. This probably reflects a direct action of the steroid at hypophyseal loci to increase GnRH receptor gene transcription. Stress-like concentrations of C suppress this estrogenic response. However, the suppressive effect of glucocorticoids is reversed with time or increased estrogenic stimulation. This transient suppression of GnRH receptor expression may explain, at least in part, the anti-gonadal effect of stress or glucocorticoids.


   FOOTNOTES
 
1 Supported by USDA Grant 93-37203-9111 and the California Agriculture Experiment Station. Back

2 Correspondence. FAX: 530 752 0175; teadams{at}ucdavis.edu Back

Accepted: September 2, 1998.

Received: July 14, 1998.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Insight into the Neuroendocrine Site and Cellular Mechanism by which Cortisol Suppresses Pituitary Responsiveness to Gonadotropin-Releasing Hormone
Endocrinology, February 1, 2008; 149(2): 767 - 773.
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K. M. Breen, C. A. Stackpole, I. J. Clarke, A. V. Pytiak, A. J. Tilbrook, E. R. Wagenmaker, E. A. Young, and F. J. Karsch
Does the Type II Glucocorticoid Receptor Mediate Cortisol-Induced Suppression in Pituitary Responsiveness to Gonadotropin-Releasing Hormone?
Endocrinology, June 1, 2004; 145(6): 2739 - 2746.
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K. M. Breen and F. J. Karsch
Does Cortisol Inhibit Pulsatile Luteinizing Hormone Secretion at the Hypothalamic or Pituitary Level?
Endocrinology, February 1, 2004; 145(2): 692 - 698.
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N. Debus, K. M. Breen, G. K. Barrell, H. J. Billings, M. Brown, E. A. Young, and F. J. Karsch
Does Cortisol Mediate Endotoxin-Induced Inhibition of Pulsatile Luteinizing Hormone and Gonadotropin-Releasing Hormone Secretion?
Endocrinology, October 1, 2002; 143(10): 3748 - 3758.
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C. Y. Williams, T. G. Harris, D. F. Battaglia, C. Viguié, and F. J. Karsch
Endotoxin Inhibits Pituitary Responsiveness to Gonadotropin-Releasing Hormone
Endocrinology, May 1, 2001; 142(5): 1915 - 1922.
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